Methanol → Methyl 2-amino-5-fluoroquinazoline-7-carboxylate

HRID 715079Notes

Reaction equation

HRID 715079 reaction equation
Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][C:8]([NH2:12])=[N:9]2)=[C:4]([F:13])[CH:3]=1.F[B-](F)(F)F.F[B-](F)(F)F.C1(P(C2CCCCC2)CCCP(C2CCCCC2)C2CCCCC2)CCCCC1.[C:53]([O-:56])([O-])=[O:54].[K+].[K+].[CH3:59]O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[NH2:12][C:8]1[N:7]=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:53]([O:56][CH3:59])=[O:54])=[CH:3][C:4]=2[F:13])[N:9]=1

Participants

7

Reactant 4

HCID 887MethanolHCID 11430Potassium CarbonateHCID 712470327-Bromo-5-fluoroquinazolin-2-amineHCID 71317487Phosphine, 1,1'-(1,3-propanediyl)bis[1,1-dicyclohexyl-, tetrafluoroborate(1-) (1:2)

Product 1

HCID 71247028Methyl 2-amino-5-fluoroquinazoline-7-carboxylateYield 59%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 6228DimethylformamideSolvent

Conditions

Temperature
100 °C

Procedure

7-Bromo-5-fluoro-quinazolin-2-amine (8.02 g, 33.1 mmol, 1.00 equiv), Pd(OAc)2 (750 mg, 3.34 mmol, 0.10 equiv), 1,3-bis(dicyclohexylphosphino)propane bis(tetrafluoroborate) (2.04 g, 3.22 mmol, 0.10 equiv) and K2CO3 (9.27 g, 66.4 mmol, 2.00 equiv) were suspended together in DMF (100 ml) under nitrogen and treated with anhydrous MeOH (13.5 mL, 333 mmol, 10 equiv). The flask was thoroughly flushed with carbon monoxide, and then heated to 100° C. with a continuous flow of carbon monoxide, which was switched to a static positive pressure on reaching temperature. After 6 h the reaction was cooled. The mixture was diluted with water (200 mL) and extracted twice into EtOAc. The combined organic phases were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford a crude orange solid (6.76 g) which was absorbed onto SiO2 and purified by automated SiO2 chromatography eluting with an EtOAc/heptane gradient (0 to 100% EtOAc) to afford 4.30 g (59%) of methyl 2-amino-5-fluoroquinazoline-7-carboxylate as a pale orange solid: 1H NMR (400 MHz, CDCl3) δ 9.35 (s, 1H), 8.07 (s, 1H), 7.48 (dd, J=10.0, 1.0 Hz, 1H), 5.35 (br s, 2H), 3.98 (s, 3H); LCMS: MH+222.2

Workup

  1. customThe flask was thoroughly flushed with carbon monoxide
  2. temperatureAfter 6 h the reaction was cooled
  3. additionThe mixture was diluted with water (200 mL)
  4. extractionextracted twice into EtOAc
  5. washThe combined organic phases were washed with water and brine
  6. dry with materialdried (Na2SO4)
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customto afford a crude orange solid (6.76 g) which
  10. customwas absorbed onto SiO2
  11. custompurified by automated SiO2 chromatography
  12. washeluting with an EtOAc/heptane gradient (0 to 100% EtOAc)

Sources & evidence

ORD record
ord-cf7a2c3a421a4155809edbe16a9eadce
Source dataset
uspto-grants-2015_11
Patent number
US09187462B2

Reaction notes

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